This invention was made with Government support under Grant No. EY016525 awarded by the National Institutes of Health. The Government has certain rights in this invention.
Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically strikes in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease was previously called Huntington's chorea. Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. Through genetic anticipation, the disease may develop earlier in life in successive generations. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid or Westphal variant HD.
The progression of HD occurs over many years and can be divided into three stages, As HD affects everyone differently, including members of the same family, people will go through the stages at different times throughout the disease. In the early stages of HD, subtle changes in mood and other psychiatric symptoms, movement, and cognition are observed. During middle stage, affected individuals lose the ability to work, drive, and need help performing activities of Daily Living. HD patients experience difficulties with balance, swallowing, voluntary motor tasks, and a growing number of psychiatric symptoms, and dementia. Individuals will have increased difficulty organizing and prioritizing information. The behavioral symptoms will affect everyone differently, but typically manifest as irritability, aggression, depression, apathy, hallucinations and delusions.
Found primarily in the cytoplasm, Httn plays a role in numerous normal functions, including the function of microtubules, vesicular membranes, and synaptic proteins. The disease is caused by an abnormal CAG repeat expansion in the HD gene (HTT), leading to the production of an expanded polyglutamine repeat in the amino terminal domain of the Huntingtin protein (Httn). Httn in Huntington's disease typically has 40 or more polyglutamine repeats. A hallmark of HD is the propensity for the mutant protein (mHttn) to misfold and aggregate. As a result of the elongated polyglutamine repeat, neurons become dysfunctional and may die. Abnormal Httn also affects the immune cells' ability to migrate in response to injury. The mutated gene prevents appropriate response to injury and infections.
There is no accurate and inexpensive diagnostic test for HD progression using cerebral spinal fluid (CSF). Such a test would allow disease prediction, improved determination of the stage of the disease, or onset of symptoms. It would also provide an assessment of the efficacy of therapies that target mutant Huntingtin protein aggregation. Prior test methods and kits for diagnosing many diseases monitor changes in proteins or enzyme activities in body fluids from patients. These methods, however, look for posttranslational changes in proteins but do not measure the consequence of any such changes.